Women are more susceptible to autoimmune diseases, and the reason is unknown. Female sex hormones appear to play a role in this predisposition to autoimmunity, but extensive analysis of the effects of the female sex steroids on immune responses in vitro have failed to identify the mechanism(s). The Richardson lab has used a new model of drug-induced lupus to identify novel gender- specific immune mechanisms. In this model, D10 cells, a cloned Th2 line, are made autoreactive by treatment with DNA methylation inhibitors, then injected into syngeneic mice. The autoreactive cells cause a more severe autoimmune disease in females than in males, and disease severity is diminished by oophorectomy. Significantly more of the cells, treated or untreated, are retained in the female spleens, and this selective retention also decreases following oophorectomy. Finally, splenectomy prevents the development of autoimmunity. These results demonstrate that T cell splenic homing differs between males and females, and that the spleen is essential for the development of disease. These results suggest that the greater disease severity in females is due to more autoreactive cells accumulating in the female spleens. The reversal by oophorectomy implicates female sex hormones in these differences. We hypothesize that gender-specific differences in T cell homing, due to effects of female sex hormones on adhesion molecule expression, contribute to increased severity of autoimmune diseases in females by modifying lymphocyte trafficking patterns. Gender-specific trafficking differences could be important both in the induction of disease as well as later in the disease process. Our model system provides a unique opportunity to directly test the role of sex hormones in modulating endothelial cell adhesion molecule expression and lymphocyte homing, and to relate these findings to the development and severity of autoimmunity. The specific aims are to: 1) Characterize the effects of sex hormones on T cell homing in vivo, 2) Define the effects of sex hormones and other signals on T cell and endothelial cell adhesion molecule expression and function in vitro, and 3) Define the role of those adhesion molecules whose expression is modified by sex hormones in splenic homing and disease severity. These studies may identify novel and important mechanisms contributing to the increased incidence and severity of autoimmune disease in women.